Human Fcxcex3 receptors (Fcxcex3R) (reviewed in Fanger, M. W., et al. (1989) Immunology Today 10:92-99), of which there are three structurally and functionally distinct types (i.e., Fcxcex3RI, Fcxcex3RII and Fcxcex3RIII), are well-characterized cell surface glycoproteins that mediate phagocytosis or antibody-dependent cell cytotoxicity (ADCC) of immunoglobulin G (IgG) opsonized targets. Antibodies have been made which are directed towards Fcxcex3R for various purposes, e.g., targeting of immunotoxins to a particular target cell type, or radioimaging a particular target cell type. The antibodies typically have been murine antibodies.
Murine monoclonal antibodies are sometimes desirable for human therapeutic applications because the antibodies can be purified in large quantities and are free of contamination by human pathogens such as the hepatitis or human immunodeficiency virus. Murine monoclonal antibodies have been used in some human therapies, however, results have not always been desirable due to the development of an immune response to the xe2x80x9cforeignxe2x80x9d murine proteins. The immune response has been termed a human anti-mouse antibody or HAMA response (Schroff, R. et al. (1985), Cancer Res., 45, 879-885) and is a condition which causes serum sickness in humans and results in rapid clearance of the murine antibodies from an individual""s circulation. The immune response in humans has been shown to be against both the variable and the constant regions of the murine immunoglobulin.
Recombinant DNA technology has provided the ability to alter antibodies by substituting specific immunoglobulin regions from one species with immunoglobulin regions from another species. Neuberger et al. (Patent Cooperation Treaty Patent Application No. PCT/GB85/00392) describes a process whereby the complementary heavy and light chain variable domains of an Ig molecule from one species may be combined with the complementary heavy and light chain Ig constant domains from another species. This process may be used to substitute the murine constant region domains to create a xe2x80x9cchimericxe2x80x9d antibody which may be used for human therapy. A chimeric antibody produced as described by Neuberger et al. would have the advantage of having the human Fc region for efficient stimulation of antibody mediated effector functions, such as complement fixation, but would still have the potential to elicit an immune response in humans against the murine (xe2x80x9cforeignxe2x80x9d) variable regions.
Winter (British Patent Application Number GB2188538A) describes a process for altering antibodies by substituting the complementarity determining regions (CDRs) with those from another species. This process may be used to substitute the CDRs from the murine variable region domains of a monoclonal antibody with desirable binding properties (for instance to a human pathogen) into human heavy and light chain Ig variable region domains. These altered Ig variable regions may then be combined with human Ig constant regions to create antibodies which are totally human in composition except for the substituted murine CDRs. The xe2x80x9creshapedxe2x80x9d or xe2x80x9chumanizedxe2x80x9d antibodies described by Winter elicit a considerably reduced immune response in humans compared to chimeric antibodies because of the considerably less murine components. Further, the half life of the altered antibodies in circulation should approach that of natural human antibodies. However, as stated by Winter, merely replacing the CDRs with complementary CDRs from another antibody which is specific for an antigen such as a viral or bacterial protein, does not always result in an altered antibody which retains the desired binding capacity. In practice, some amino acids in the framework of the antibody variable region interact with the amino acid residues that make up the CDRs so that amino acid substitutions into the human Ig variable regions are likely to be required to restore antigen binding.
The present invention pertains to humanized antibodies specific to an Fc receptor (FcR). The humanized antibodies have at least a portion of a complementarity determining region (CDR) derived from a non-human antibody, e.g., murine, with the remaining portions being human in origin. The use of humanized antibodies rather than murine antibodies in human therapy should alleviate some of the problems associated with the use of some murine monoclonal antibodies because only the substituted CDRs will be foreign to a human host""s immune system.
The present invention farther pertains to the use of humanized antibodies specific to an FcR as components in heteroantibodies, bifunctional antibodies, or immunotoxins. The humanized antibody specific to an FcR may be used in the same manner and for the same purpose as its corresponding murine counterpart. For example, the humanized anti-Fc receptor antibody of this invention can be used to treat cancer, allergies, and infectious and autoimmune diseases. Diagnostic applications of the antibodies include their use in assays for FcRI levels and assays for substances that influence FcR levels.